My laboratory is focused on the hypothesis that B-cell tumor-derived Ig idiotype(Id) can serve as a tumor-specific antigen for therapeutic vaccine development. Our underlying scientific hypothesis is that sustained, potent, T-cell-mediated responses, especially CD8+ T cell responses, will be required for achieving the eventual goal of demonstrating clinical efficacy. Our principal objective has been to obtain conclusive proof for the general cancer vaccine concept; i.e., simply that it is possible to induce an immune response against a self protein, which is inherently poorly immunogenic. Our recently completed single-arm Phase II clinical trial of Id-KLH+GM-CSF vaccination in previously untreated patients with FOLLICULAR LYMPHOMAS (FL) has accomplished this first goal. This carefully designed treatment protocol produced a homogeneous group of patients, all in a minimal residual disease state first complete clinical remission (CR) following uniform chemotherapy, who were given vaccine treatment. The selection of GM-CSF as the immunological adjuvant; was a direct extension of our laboratory studies in small animal models demonstrating that GM-CSF can enhance the potency of the prototype Id-KLH vaccine by augmenting almost exclusively the cellular arm of the immune response. This Phase II study demonstrated CD4+ and CD8+ T cell responses which were capable of lysing autologous tumor in the majority of cases and provided systematic evidence for anti-tumor effects, based on the achievement of molecular remissions, both firsts for a lymphoma vaccine. These compelling results (published in Nature Medicine, 5:1171-1177,1999)have provided a basis on which to build future clinical research aims. In particular, a multicenter, randomized, controlled Phase III clinical trial, designed to provide the definitive answer to the question of whether clinical benefit can be demonstrated, was established independently as an NCI IMPACT project. This Phase III trial opened in January 2000 at a consortium of extramural centers, including Moffitt Cancer Center, Northwestern University, Duke Comprehensive Cancer Center and University of Pennsylvania. In addition, this formulation can potentially serve as a positive control; when applied clinically to other, selective disease indications. Specifically, FL was selected as the first disease target, in large part because the malignant cells are derived from mature germinal center B cells which have a relatively high density of intact Ig on the surface. Future trials planned in CLL (which express relatively less intact surface Ig as a target) and efforts already underway in MULTIPLE MYELOMA (absence of intact surface Ig on the tumor cell surface), represent a rational, stepwise approach testing the underlying hypothesis that T cell responses are principally important for clinical efficacy. Furthermore, a recently initiated pilot clinical protocol employing the Id-KLH+GM-CSF vaccine formulation in MANTLE CELL LYMPHOMA patients will provide the most rigorous test of this underlying hypothesis. MCL comprises approximately 4% of all lymphomas in the U.S. However, it represents a major therapeutic challenge, because its clinical behavior is aggressive, and it is incurable with current available therapies, with a median survival of 3-4 years. Id vaccination represents a novel treatment modality which has not been evaluated in aggressive lymphomas. A major strength of this study design is that the Id-KLH+GM-CSF vaccine formulation, which elicited CD8+ T cell immunity in the Phase II follicular, low-grade lymphoma study, can serve as a positive control. The pilot study in MCL has also been rationally designed using other principles in common with the Phase II follicular lymphoma study. For example, patients will first receive 4-6 cycles of uniform induction chemotherapy (EPOCH-Rituxan), designed to produce a homogeneous patient population, all in a minimal residual disease state at the time Id vaccination is administered. Patients will be monitored before and after vaccination for tumor-specific T-cell responses.